Synaptic mechanisms of stress-induced hypertension Project Summary Hypertension is one of the most prevalent health problems and a well-recognized risk factor for many fatal diseases. Thus, it is crucial to identify the mechanisms responsible for the development of hypertension. Prolonged and repeated exposure to stress may cause chronic elevation of sympathetic nerve activity, which contributes to the development of hypertension. Individuals with a genetic predisposition to hypertension may develop a sustained elevation of arterial blood pressure even after removal of the stressor. However, little is known about the neural mechanisms underlying chronic- stress?induced persistent hypertension. Our long-term goal is to determine the synaptic mechanisms involved in stress-induced hypertension. This project will use borderline hypertensive rats (BHRs), the first-generation offspring of cross-breeding of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats, to explore the molecular mechanism responsible for chronic stress-induced hypertension. The paraventricular nucleus (PVN) of the hypothalamus is a key brain site that mediates the stress response and is an important source of the excitatory drive that heightens sympathetic vasomotor tone in the development of hypertension. The preliminary studies showed that chronic stress increased the expression level of ?2?-1 in the PVN, which in turn interacts with the glutamate N-methyl- D-aspartate receptor (NMDAR) to increase its synaptic activity. The central hypothesis is that chronic stress transforms borderline hypertension into persistent hypertension through upregulation of ?2?-1 in the PVN, which interacts with NMDARs and leads to enhanced synaptic NMDAR trafficking and heightened sympathetic outflow. The hypothesis will be tested through pursuit of the following 3 specific aims: 1. Determine the extent to which chronic stress upregulates the expression levels of ?2?-1 and NMDARs in the PVN in BHRs. 2. Determine the role of ?2?-1 in the PVN in chronic stress-induced sustained hypertension in BHRs. 3. Determine whether ?2?-1 interacts with NMDARs and the role of ?2?-1 in enhanced NMDAR activity of PVN presympathetic neurons in BHRs with chronic stress- induced sustained hypertension. The proposed work is innovative because it will be the first study to investigate the interactions between ?2?-1 and NMDARs in the PVN in chronic stress?induced hypertension. The proposed work is highly significant because it will not only identify new molecular mechanisms underlying stress-induced hypertension but also may lead to the development of new treatments for neurogenic hypertension. 1